ABSTRACT Synucleinopathies are neurodegenerative diseases with abnormal accumulation of ?-synuclein within cytoplasmic inclusion in neurons or oligodendroglia. Synucleinopathies with intraneuronal ?-synuclein deposits, which aggregate into Lewy bodies, include Parkinson disease (PD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). In multiple system atrophy (MSA) ?-synuclein accumulates primarily in oligodendroglia. A characteristic feature of the synucleinopathies is that they can all begin with varying degrees of autonomic dysfunction as the sole clinical feature ? implying an initial diagnosis of pure autonomic failure.1 After a variable period of time, but usually less than 5 years, only a small number of patients remain with a pure autonomic failure phenotype, but careful follow-up is lacking.1 Most patients develop cognitive or motor abnormalities (or both) and the patient is then diagnosed with PD, DLB or MSA. This stepwise clinical progression suggests that the neurodegenerative process can in rare cases remain confined to autonomic neurons,2 but more frequently spreads to affect additional areas of the central nervous system (CNS). This unique feature of the synucleinopathies poses diagnostic challenges and potential therapeutic opportunities. The challenges are first, to determine whether PAF is a distinct disease or is always a prodromal phase of PD, DLB or MSA and second, to discover biomarkers that predict spread to motor and cognitive neurons. Such biomarkers would allow testing of disease-modifying strategies to delay or stop the neurodegenerative process in the pre-motor or pre-dementia phase. Obstacles to identifying biomarkers predicting further CNS involvement are that most medical centers only see patients with synucleinopathies when they already have developed motor and cognitive involvement, and that PAF and MSA are rare disorders. In this context the Autonomic Disorders Consortium (ADC) within the Rare Diseases Clinical Research Network (RDCRN) of the National Institutes of Health (NIH) was created with the objective of providing a better understanding of the variability, progression, and natural history of neurodegenerative synucleinopathies. In our previous funding period we have recruited and carefully phenotyped a large cohort of synucleinopathy patients at different clinical stages into a prospective longitudinal observational study. In particular, we have enrolled the largest ever cohort of patients with the PAF phenotype. Preliminary analyses of data already obtained from follow-up evaluations have led us to hypothesize that particular clinical and laboratory biomarkers may be predictive of future evolution of patients with the PAF phenotype to PD, DLB or MSA. Continuing this observational study, and increasing its power by including additional academic centers from the U.S., South America, and Europe, will allow us to define the natural history of these diseases and establish the sensitivity and specificity of the proposed biomarkers.